Investigations will be conducted of the grave problem of human adenocarcinomas of the large bowel (in which clinical responses to drugs are both relatively infrequent and always incomplete), through the use of such human carcinomas, grown both in cell culture and in mice partially immunosuppressed with frequent injections of anti-thymocyte serum (ATS) produced in such species as the rabbit and the goat. Chemotherapeutic and biochemical studies will be carried out both in culture and in mice bearing human carcinomas, with the primary goal being the attainment of long-term or permanent regressions, particularly of metastatic foci, whether naturally occurring or artificially induced. Extensive biochemical investigations will seek to explain the mechanisms of the occasional sensitivity to 5-fluorouracil, and the much more frequent lack of response that follows the use of this and other drugs, given either alone or in combinations. Major efforts will be made to design more nearly optimal combinations of drugs for the therapy in mice of primary or metastatic human carcinomas of the large bowel, with attention to regimens of dosage, spacing of doses, simultaneous vs. sequential administration, etc. The drugs to be studied will include 5-fluorouracil and derivatives thereof, methotrexate, cytosine arabinoside and adenine arabinoside, cyclophosphamide and phosphamide mustard, as well as three groups of new compounds, now being synthesized in the department (of which the most promising appear to be analogs of pyrazofurin), which compounds have been designed to inhibit the salvage by neoplastic cells of pre-formed pyrimidines, especially uridine, while these essential precursors of nucleic acids are formed by most normal cells through biosynthesis de novo, thereby affording an opportunity for a selective attack upon cancer cells.